PROJECT THREE SUMMARY/ABSTRACT The central theme of the MADRC is to examine the earliest features of the Alzheimer disease process. In keeping with this theme, the Center aims to understand dysfunction in neural systems prior to overt clinical symptoms - using novel clinical assays, advanced neuroimaging, and neuropathological studies focused on amyloid positive, cognitively intact individuals. Animal models would be an additional important approach to these early phases of disease where there is a gap in our knowledge; unfortunately, although animal models develop amyloid plaques and/or neurofibrillary tangles and reliably reproduce the molecular pathology of AD, they do not reproduce the unique patterns of anatomical changes that occur in early AD. Thus, no current animal models of AD provide a platform to study the anatomically restricted pathological changes that are known to occur in human patients. To address this problem, therefore, we have generated a transgenic mouse line (rTauEC) that over-expresses human mutant P301L tau primarily in the medial entorhinal cortex and develops tangles in those neurons in a pattern that is reminiscent of the early Braak II stage of human AD. We will examine the natural history of this model, examining the temporal relationship of tangles, synapse loss, and neuronal loss, to get at chicken-and-egg issues not possible to disambiguate in human autopsy tissue. We will use behavioral paradigms and molecular markers of neural system activation to test hypotheses about functional deafferentation of neural systems at early time points, before onset of behavioral abnormalities. Entorhinal neurons in rTauEC mice develop aberrant tau-filled axons and altered axonal projections, ultimately losing synaptic terminals in the dentate gyrus. This model also has the attribute of developing tau inclusions in the neurons that are the target of the entorhinal projection, in the dentate gyrus, despite not expressing human tau mRNA in those neurons. This has been interpreted as supporting the idea that there is a trans-synaptic propagation of pathological tau. We have crossed the rTauEC mice with APP/PS1 overexpressors to develop a model of tangles in entorhinal cortex and plaques throughout the cortex, analogous to the human pathology of many early cases of AD changes. Surprisingly, the addition of plaques seems to robustly accelerate the tangle propagation phenotype and also exacerbate the axonal dystrophies, developing more severe neuritic lesions in the hippocampus. Tau overexpression can be regulated with doxycycline in the rTau EC mice, mimicking some forms of anti-tau therapies. This model will therefore allow us to dissect a detailed time course of neural system degeneration, test hypotheses about tau-amyloid interactions in a defined neural system, and examine the consequences of reducing tau at various points in the disease process. Together these experiments will help provide insight into the pathobiology of the earliest phases of AD as well as highlight potential opportunities for therapeutic intervention early in the disease.